Atherosclerosis (AT) results from an excessive inflammatory and fibroproliferative response to vascular insult and has been noted to be a principal cause of heart attack and stroke, accounting for up to half of all mortalities in the industrialized world including about 13 million Americans. Atherogenesis is theorized to follow a response to injury, but the agent(s) of injury have yet to be identified fully.
Viral and/or bacterial infection(s) have been found to be associated in some way with the complex process of the development of AT. Particles, antigens and DNA sequences of human cytomegalovirus (HCMV), a member of the herpesvirus group, have been described in AT plaques of biopsy or autopsy material [M. G. Hendrix et al, Am. J. Pathol., 136:23-28 (1990); J. L. Melnick et al., BioEssays, 17(10): 899 (October 1995)]. However, Melnick, cited above, states that the "observations do not demonstrate a viral role in the pathogenesis of atherosclerosis". The possible involvement of reactivated HCMV in restenosis of coronary arteries, an accelerated form of AT, following angioplastic surgery has been suggested [S. E. Epstein et al, Lancet, 348:13-17 (1996); E. Speir et al, Science, 265:391-394 (1994); Y. F. Zhou et al, N. Engl. J. Med., 335: 624-630 (1996)]. Seroepidemiologic data show that HCMV infection usually occurs in childhood, paralleling the pattern of the appearance of early AT lesions; by young adulthood, 50-100% of individuals are HCMV-seropositive. In some individuals, the virus is apparently reactivated in artery walls, where it may initiate abnormal cell growth that can lead to blocked blood flow and, ultimately, heart attack.
The bacterium Chlamydia pneumoniae is an intracellular bacterium, which has been established as an important pathogen in acute and chronic respiratory infections [J. T. Grayson, Clin. Infect. Dis., 15:757-763 (1992)] has also been associated with AT [J. A. Ramirez, Ann. Intern. Med., 125:979-982 (1996)]. This bacterium infects about 50% of the population and causes flu-like diseases, but also replicates in the arterial wall. C. pneumoniae antigens and DNA have been detected in human AT plaques. Population antibody prevalence studies have shown that more than 50% of adults worldwide have antibody. While antibody is infrequent in children under age 5 years, incidence studies have demonstrated antibody conversion of 6-9% per year in children from the ages 5-14 years. The prevalence of antibody continues to increase throughout adulthood, and is highest in the elderly.
Recently, C. pneumoniae, strain TWAR, has been associated with AT based on both seroepidemiology and data demonstrating the presence of the organism in AT plaques. For example, serologic studies from Finland, the United States and other countries have shown that patients with coronary artery diseases were significantly more likely to have serologic evidence of past infection with TWAR than were controls. Morphologic and microbiological evidence of the persistence of TWAR in atheromatous plaques has been obtained by electron microscopic studies, immunochemical staining and PCR testing of coronary, carotid and aortic atheroma [C.-C. Kuo et al, Clin. Microbiol. Rev., 8:451-461 (1995)]. In addition, C. pneumoniae activates growth factors involved in inflammatory responses and changes lipoprotein metabolism of infected cells. Immune responses to chlamydial infections are partly protective but also deleterious, and delayed hypersensitivity (DH) is thought to play a pathogenic role in chlamydial disease [R. P. Morrison et al, J. Exp Med., 170:1271-1283 (1989)].
Despite the wealth of reports, no etiological role of HCMV and/or C. pneumoniae in the development of AT has been established. Thus, there remains a need in the art for reagents and methods useful in ameliorating the symptoms and development of atherosclerosis in response to these microorganisms.